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1.
Cancer Sci ; 111(2): 429-440, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808966

RESUMO

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3ß, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3ß in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3ß (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3ß activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3ß inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3ß in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3ß as a new and promising therapeutic target for these STS types.


Assuntos
Fibrossarcoma/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Indóis/administração & dosagem , Maleimidas/administração & dosagem , Sarcoma Sinovial/tratamento farmacológico , Tiazóis/administração & dosagem , Ureia/análogos & derivados , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Indóis/farmacologia , Injeções Intraperitoneais , Maleimidas/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Tiazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Radiat Oncol Biol Phys ; 106(3): 546-555, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730876

RESUMO

PURPOSE: Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease. METHODS AND MATERIALS: A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized. RESULTS: Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score <7 (95%). Median prostate-specific antigen at diagnosis was 7.4 ng/mL and at relapse was 4.8 ng/mL. DI detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 9 out of 79 (11%), distant disease in 12 out of 79 (15%), and no disease in 26 out of 79 (33%). 18F-DCFPyL PET/CT detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 21 out of 79 (27%), distant disease in 24 out of 79 (30%), and no disease in 10 out of 79 (13%). DI identified 8 out of 79 (10%) patients to have oligometastatic disease, compared with 21 out of 79 (27%) with 18F-DCFPyL PET/CT. 18F-DCFPyL PET/CT changed proposed management in 34 out of 79 (43%) patients. CONCLUSIONS: 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men.


Assuntos
Lisina/análogos & derivados , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/sangue , Radioisótopos de Flúor , Glutamato Carboxipeptidase II/sangue , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia
3.
Eur J Med Chem ; 186: 111896, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31784185

RESUMO

We report here a thorough structure-activity relationship (SAR) with piperazinylureido sulfamates as inhibitors of human (h) carbonic anhydrase (CA, EC 4.2.1.1). A SAR investigation over the structure of reported anti-cancer zinc-binder CAIs such as SLC-0111 and S4 was carried out by including the urea outer nitrogen atom into a substituted piperazine ring reducing the linker flexibility. The derivatives were assessed for the inhibition of CA I, II and IV (off-target isoforms) and the tumor-associated CA IX (anticancer drug target). CA I and IV were not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against CA II (KIs in the range of 1.0-705.5 nM), and IX (KIs in the range of 0.91-155.9 nM). Interestingly, a subset of CA II/IX selective inhibitors was detected which might represent interesting lead for the development of new anticancer strategies.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Ácidos Sulfônicos/farmacologia , Ureia/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Ácidos Sulfônicos/química , Ureia/análogos & derivados , Ureia/química
4.
Eur J Med Chem ; 187: 111973, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881453

RESUMO

Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including ß-thalassemia. Small molecule activators of HRI are essential for studying normal- and patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2α may be beneficial. We previously reported development of 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2α phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2α phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.


Assuntos
Antineoplásicos/farmacologia , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Heme/antagonistas & inibidores , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Iniciação 2 em Eucariotos/metabolismo , Heme/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
5.
Eur J Med Chem ; 187: 111971, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881457

RESUMO

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Drogas , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
6.
J Enzyme Inhib Med Chem ; 35(1): 404-413, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880473

RESUMO

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.


Assuntos
Helicobacter pylori/efeitos dos fármacos , Ureia/farmacologia , Urease/antagonistas & inibidores , Antibacterianos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Helicobacter pylori/citologia , Helicobacter pylori/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Urease/metabolismo
7.
Int J Antimicrob Agents ; 55(3): 105865, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31866465

RESUMO

BACKGROUND: Candida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains. OBJECTIVE: A compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety. METHODS: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution. RESULTS: The current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. CONCLUSIONS: The results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Guanidina/análogos & derivados , Ureia/análogos & derivados , Animais , Antifúngicos/uso terapêutico , Azóis/farmacologia , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica/efeitos dos fármacos , Guanidina/farmacologia , Guanidina/uso terapêutico , Testes de Sensibilidade Microbiana , Ratos , Ureia/farmacologia , Ureia/uso terapêutico
8.
Eur J Med Chem ; 185: 111840, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711794

RESUMO

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 µM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs.


Assuntos
Adenovírus Humanos/efeitos dos fármacos , Antivirais/farmacologia , Piperazinas/farmacologia , Ureia/farmacologia , Células A549 , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
9.
Food Chem ; 302: 125371, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437711

RESUMO

Dietary selenium deficiency is recognized as a global problem. Pork is the most widely consumed meat throughout the world and an important source of selenium for humans. In this study, a reliable approach was developed for analyzing selenium and its speciation in the muscles of pigs after different selenium treatments. The selenium source deposition efficiency was ranked as: selenomethionine > methylselenocysteine > selenite, and the muscle selenium content had a dose effect with selenomethionine supplementation. In total, four species of selenium were detected in the muscles of pigs and the distributions of these selenium species were greatly affected by the dietary selenium supplementation forms and levels. Selenomethionine (>70% of total selenium) and selenocystine (>11%) were the major selenium species, followed by methylselenocysteine and selenourea. Therefore, selenium-enriched pork produced from selenomethionine is a good source for improving human dietary selenium intake.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Músculo Esquelético/química , Compostos de Selênio/farmacologia , Selênio/análise , Animais , Cistina/análogos & derivados , Cistina/análise , Suplementos Nutricionais , Análise de Alimentos/métodos , Masculino , Músculo Esquelético/efeitos dos fármacos , Compostos Organosselênicos/análise , Reprodutibilidade dos Testes , Ácido Selenioso/farmacologia , Compostos de Selênio/análise , Selenocisteína/análogos & derivados , Selenocisteína/farmacologia , Selenometionina/análise , Selenometionina/farmacologia , Suínos , Ureia/análogos & derivados , Ureia/análise
11.
PLoS Pathog ; 15(10): e1008068, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31648236

RESUMO

Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.


Assuntos
Linfócitos T CD4-Positivos/virologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Linfopenia/imunologia , Replicação Viral/fisiologia , Animais , Antígenos Virais/biossíntese , Antígenos Virais/genética , Autofagia/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Estresse do Retículo Endoplasmático/fisiologia , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Indóis/farmacologia , Células Jurkat , Proteína Fosfatase 1/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Viral/biossíntese , RNA Viral/genética , Fatores de Transcrição/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Células Vero , Proteínas Virais/metabolismo
12.
Eur J Med Chem ; 183: 111741, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605873

RESUMO

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.


Assuntos
Antineoplásicos/síntese química , Carbazóis/síntese química , Macrófagos/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/síntese química , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Feminino , Humanos , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Relação Estrutura-Atividade , Microambiente Tumoral , Ureia/administração & dosagem , Ureia/farmacologia
13.
Adv Clin Exp Med ; 28(10): 1393-1401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518496

RESUMO

BACKGROUND: Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure. OBJECTIVES: The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed. RESULTS: Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression. CONCLUSIONS: Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.


Assuntos
Ciclosporina/toxicidade , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Urotensinas/antagonistas & inibidores , Animais , Creatinina/sangue , Creatinina/urina , Ciclosporina/efeitos adversos , Imunossupressores , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Modelos Animais , Quinolinas , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Ureia/análogos & derivados
14.
Chem Biodivers ; 16(12): e1900461, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557406

RESUMO

The discovery of new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a-10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1'-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis ß-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds.


Assuntos
Antibacterianos/síntese química , Dissulfetos/química , Ureia/análogos & derivados , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Animais , Antibacterianos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Células RAW 264.7 , Relação Estrutura-Atividade , Ureia/farmacologia
15.
Dtsch Med Wochenschr ; 144(18): 1280-1285, 2019 09.
Artigo em Alemão | MEDLINE | ID: mdl-31514219

RESUMO

Supraventricular tachyarrhythmias, especially atrial fibrillation, are common in cardiac and non-cardiac patients with or without surgery. Prolonged rhythm disturbances may impair cardiac function and worsen the clinical outcome and prognosis. Therefore, heart rate control may be necessary to prevent cardiovascular events.Esmolol and landiolol as ultrashort and rapid acting highly selective ß 1 -adrenergic blockers are of particular interest in the prevention and management of cardiac arrhythmias. This review gives an update on both betablockers and their role in the management of arrhythmias in emergency medicine and perioperative setting.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Estado Terminal/terapia , Morfolinas/uso terapêutico , Propanolaminas/uso terapêutico , Ureia/análogos & derivados , Fibrilação Atrial/tratamento farmacológico , Humanos , Ureia/uso terapêutico
16.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514437

RESUMO

There is robust evidence indicating that enhancing the endocannabinoid (eCB) tone has therapeutic potential in several brain disorders. The inhibition of eCBs degradation by fatty acid amide hydrolase (FAAH) blockade, is the best-known option to increase N-acyl-ethanolamines-(NAEs)-mediated signaling. Here, we investigated the hypothesis that intranasal delivery is an effective route for different FAAH inhibitors, such as URB597 and PF-04457845. URB597 and PF-04457845 were subchronically administered in C57BL/6 male mice every other day for 20 days for overall 10 drug treatment, and compared for their ability to inhibit FAAH activity by the way of three different routes of administration: intranasal (i.n.), intraperitoneal (i.p.) and oral (p.o.). Lastly, we compared the efficacy of the three routes in terms of URB597-induced increase of NAEs levels in liver and in different brain areas. Results: We show that PF-04457845 potently inhibits FAAH regardless the route selected, and that URB597 was less effective in the brain after p.o. administration while reached similar effects by i.n. and i.p. routes. Intranasal URB597 delivery always increased NAEs levels in brain areas, whereas a parallel increase was not observed in the liver. By showing the efficacy of intranasal FAAH inhibition, we provide evidence that nose-to-brain delivery is a suitable alternative to enhance brain eCB tone for the treatment of neurodegenerative disorders and improve patients' compliance.


Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Amidoidrolases/metabolismo , Animais , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Carbamatos/administração & dosagem , Carbamatos/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Endocanabinoides/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologia
17.
Pharmacol Biochem Behav ; 185: 172761, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31425712

RESUMO

Alcohol use is frequently associated with mood disorders. Similarly, individuals suffering from these disorders have a higher risk of developing alcoholism. Several reports have implicated orexin signaling in different behaviors related to alcohol consumption, whereas antagonists block these actions. However, the involvement of orexin-1-receptor (Orx1R) in ethanol-induced anxiolysis remains relatively unexplored. The purpose of this study was to investigate whether intra-accumbal inhibition of Orx1R blocks the anxiolytic-like effect of ethanol and to determine if ethanol administration modifies orexin-A content and Orx1R expression in the nucleus accumbens (NAc). The elevated-plus-maze test (EPM-test) was used to measure anxiety; orexin-A content and Orx1R expression were determined by enzyme-immunoassay and western blot, respectively. The results showed that the pretreatment with a selective antagonist of Orx1R, SB-334867 (SB, 3 µg/side), prevents the anxiolytic-like behavior induced by acute ethanol (2.5 g/kg). SB-334867 per se had no effect on anxiety levels. Pretreatment with SB-334867 followed by ethanol (SB + Et) increased orexin-A content and Orx1R levels in the NAc in comparison to the groups that only received ethanol (V + Et) or SB-334867 (SB + S). Ethanol treatment significantly augmented Orx1R expression but not the peptide content. The increase in orexin-A observed in SB + Et animals could be due in part to the inhibition of Orx1R, since SB-334867 prevents the binding of orexin-A to the receptor. This increase in orexin-A may, in turn, induce an up-regulation of receptor. Other possible explanations were discussed. In general, these findings suggest that orexin-A contributes largely to expression of ethanol-induced anxiolytic-like effect through the signaling of Orx1R in the NAc.


Assuntos
Ansiolíticos/farmacologia , Benzoxazóis/farmacologia , Etanol/farmacologia , Naftiridinas/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ureia/análogos & derivados , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Etanol/administração & dosagem , Modelos Lineares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/administração & dosagem , Núcleo Accumbens/metabolismo , Antagonistas dos Receptores de Orexina/administração & dosagem , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia
18.
Eur J Med Chem ; 182: 111614, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422224

RESUMO

Two new piperazinyl-ureido single ring aryl sulfamate-based inhibitor series were designed against the emerging oncology drug target steroid sulfatase (STS), for which there are existing potent steroidal and non-steroidal agents in clinical trials. 4-(Piperazinocarbonyl)aminosulfamates (5-31) were obtained by reacting 4-hydroxyarylamines with phenylchloroformate, subsequent sulfamoylation of the resulting hydroxyarylcarbamates and coupling of the product with 1-substituted piperazines. Pyrimidinyl-piperazinourea sulfamates (35-42) were synthesized by pyrimidine ring closure of 4-Boc-piperazine-1-carboxamidine with 3-(dimethylamino)propenones, deprotection and coupling with the sulfamoylated building block. Target ureidosulfamates 5-31 and 35-42 were evaluated both as STS inhibitors in vitro using a lysate of JEG-3 human placenta choriocarcinoma cell line and in a whole cell assay. SAR conclusions were drawn from both series. In series 35-42 the best inhibitory activity is related to the presence of a benzofuryl on the pyrimidine ring. In series 5-31 the best inhibitory activity was shown by the ureas bearing 4-chlorophenyl, 3,4-dichlorophenyl groups or aliphatic chains at the piperazino 4-nitrogen displaying IC50 in the 33-94 nM concentration range. Final optimization to the low nanomolar level was achieved through substitution of the arylsulfamate ring with halogens. Four halogenated arylsulfamates of high potency were achieved and two of these 19 and 20 had IC50 values of 5.1 and 8.8 nM respectively and are attractive for potential in vivo evaluation and further development. We demonstrate the optimization of this new series to low nanomolar potency, employing fluorine substitution, providing potent membrane permeant inhibitors with further development potential indicating piperazinyl-ureido aryl sulfamate derivatives as an attractive new class of STS inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Esteril-Sulfatase/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Ureia/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Esteril-Sulfatase/metabolismo , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química , Ureia/análogos & derivados , Ureia/química
19.
Diab Vasc Dis Res ; 16(6): 523-529, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31267765

RESUMO

The impact of the local inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide hydrolase inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.


Assuntos
Benzoatos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Epóxido Hidrolases/antagonistas & inibidores , Microcirculação/efeitos dos fármacos , Ureia/análogos & derivados , Administração Cutânea , Animais , Velocidade do Fluxo Sanguíneo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/enzimologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Géis , Masculino , Camundongos Endogâmicos C57BL , Fluxo Sanguíneo Regional , Transdução de Sinais , Sus scrofa , Ureia/administração & dosagem
20.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288375

RESUMO

Ureido-N-iso-propyl,N'-4-(3-pyridin-2-one)pyrimidine (1) and its 2-methoxy pyridine derivative (1Me) has been designed and prepared. The conformational equilibrium in urea moiety and tautomerism in the pyrimidine part have been investigated by variable temperature and 1H NMR titrations as well as DFT quantum chemical calculations. The studied compounds readily associate by triple hydrogen bonding with 2-aminonaphthyridine (A) and/or 2,6-bis(acetylamino)pyridine (B). In 1, the proton is forced to 1,3-tautomeric shift upon stimuli and keeps it position, even when one of the partners in the complex was replaced by another molecule. The observed tautomerism controlled by conformational state (kinetic trapping effect) opens new possibilities in molecular sensing that are based on the fact that reverse reaction is not preferred.


Assuntos
Pirimidinas/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Catálise , Ligações de Hidrogênio , Isomerismo , Cinética , Conformação Molecular , Prótons , Teoria Quântica , Temperatura Ambiente , Termodinâmica
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